1. Field of the Invention
This invention is in the field of synthetic chemistry. More particularly, it relates to a new method and to new reagents for introducing the fluoromethyl group, --CH.sub.2 F, onto carbonyl carbons in organic structures. These new reagents are most specifically embodied as magnesium benzylfluoromalonates.
2. Description of Background Information
Fluorination of organic compounds poses several difficulties. For one, the classic methods of fluorination typically employ harsh conditions which can be destructive or disruptive to many organic structures. Similarly, the reagents employed in many fluorinations are often hazardous and difficult to work with safely. This can render scale-up of reactions problematic. In addition, the unique electronic properties of the fluorine atom and its effects on neighboring groups make it difficult to analogize fluorination reactions with other, seemingly similar, reactions such as chlorinations.
Nonetheless, selective monofluorination of organic compounds has become an area of increasingly great interest in recent years (Haas, A.; Lieb, M. Chimia, (1985), 39, 134; Rozen, S.; Filler, R.; Tetrahedron, (1985), 41, 1111; Purrington, S. T.; Kagen, B. S.; Patrick, T. B. Chem. Rev., (1986), 86, 997). In light of the vast potential of fluorinated compounds of medicinal and biological interest (Welch, J. T. Tetrahedron, (1987), 43, 3123), new methods for introduction of a single fluorine atom into various species are in high demand. Several new methods have been recently published, including the use of dilute elemental fluorine, (Purrington, S. T.; Lazaridis, N. V.; Bumgardner, C. L. Tetrahedron Lett., (1986) 27, 2715. Purrington, S. T.; Bumgardner, C. L.; Laziridis, N. V.; Singh, P. J. Org. Chem., (1987), 52, 4307)) and N-fluorinated species (Umemoto, T.; Tomita, K. Tetrahedron Lett., (1986), 27, 3171. Umemoto, T.; Kawada, K.; Tomita K. Tetrahedron Lett., (1986), 27, 4465. Lang, R. W.; Differding, E. Tetrahedron Lett., (1988), 29, 6087) as sources of electrophilic fluorine.
In many cases, particularly as related to compounds of biological interest, it is necessary to have a method for introducing fluoromethyl groups into stereospecific organic molecules. In the area of peptide analog synthesis there is a need for an extremely mild method for transforming alpha-amino acids to the corresponding fluoromethyl ketones without disrupting the alpha-amino acid's stereochemistry. The need to maintain stereochemical integrity in the amino acid makes this transformation particularly difficult. A modified Dakin-West reaction (Rasnick, D. Analytical Biochem, (1985), 149: 461) that has been used to effect this type of transformation is limited not only by the necessary loss of stereochemistry at the amino acid residue as a result of the proposed mechanism (Wiley, R. H.; Borum. O. H. Org. Syn., (1963), Coll. Vol. 4: 5), but also by the sterics of the alkyl residue in question.
The present invention provides an extremely mild stereoselective method for introducing fluoromethyl groups into organic compounds. It employs a reactive metal salt of an aryl or aralkyl fluoromalonate. In 1979, Brooks and Masamune (Brooks, D. W.; Lu. L.; Masamune, S. Angew. Chem. Int. Ed. Eng., (1979), 18: 72) reported the use of magnesium malonates to introduce methyl and alkyl-substituted methyl groups into organic structures. The reaction of the carboxyl group with the malonate and the placement of the methyl or alkyl-substituted methyl on the carboxyl carbonyl is shown in Equation 1. ##STR1##
The use of this methodology to introduce these simple alkyl groups is well documented. (See, e.g., Bodurow, C. C., et al. Tetrahedron Lett., (1989), 30, 2321. Mansour, T. S. Synth. Commun., (1989), 659. Hashiguchi, S.; Natsugari, H.; Ochiai, M. J. Chem. Soc. Perkin Trans. I., (1988), 2345. Maibaum, J.; Rich, D. H. J. Org. Chem., (1988), 53, 869. Ha, D. C.; Hart, D. J. J. Antibiotics, (1987), 40, 309. Liu, L.; Tanke, R. S.; Miller, M. J. J. Org. Chem. (1986), 51, 5332. Nagahara, T.; Kametani, T. Heterocycles, (1987), 25, 729. Brooks, D. W.; Palmer. J. T. Tetrahedron Lett., (1983), 24, 3059. Pollet, P. L. J. Chem. Ed. (1983), 60, 244. Kametani, T.; Fukumoto, K.; Ihara, M. Heterocycles, (1982), 17, 463. Melillo, D. G.; Liu, T.; Ryan, K.; Sletzinger, M.; Shinkai, I. Tetrahedron Lett., (1981 ), 22, 913. Salzmann, T. N.; Ratcliffe, R. W.; Christensen, B. G.; Bouffard, F. A. J. Am. Chem. Soc. (1980), 102, 6161). However, this chemistry has not been demonstrated to be applicable with alpha substituents other than alkyl groups or hydrogen. Moreover, the reagents needed to carry out fluoromethylations with this type of chemistry have not been available.